This invention relates to a process for fluorinating halogenated ether compounds, more particularly the replacement of one or more chloro atoms alpha to an ether oxygen by a fluoro atom. This process is especially useful for the synthesis of valuable inhalation anesthetics.
Although the most direct route to the preparation of fluorine containing organic compounds may be the replacement of hydrogen in an organic compound, such a reaction is problematic. It is well known that the reaction of elemental fluorine with organic compounds to replace hydrogen with fluorine is problematic. Partially fluorinating organic compounds, so as to have fluorine atoms in the desired positions, is usually not possible in satisfactory yields. Although certain halogens other than fluorine, e.g. chlorine and bromine, generally react well with a wide variety of organic compounds under moderate conditions to give high yields, the reaction of fluorine is usually violent and accompanied by the formation of undesirable and unrecyclable side products.
Besides elemental fluorine, other agents have been tried to selectively replace hydrogen with fluorine. Among the fluorinating agents tried have been hydrogen fluoride, cobalt trifluoride, silver difluoride, etc. However, little success has been reported in attempting to selectively replace hydrogen with fluorine.
For the above reasons, it is generally preferable to first prepare a corresponding chloro compound and then replace the chloro atom with a fluoro atom. Metal fluorides have heretofore been proposed in general to replace chlorine with fluorine in organic compounds. For example, British patent specification 727,768 discloses the preparation of fluoroesters, ethers, and acetals with potassium fluoride in the presence of a solvent containing acetamide and/or N-methyl acetamide.
In Tetrahedron Lett, 27(13), 1499-500 (1986), Escoula et al. disclose a fluoride-chloride exhange reaction employing potassium fluoride, catalyzed by ammonium salts in the presence of formamide in place of water. Monochloroctane is an exemplary starting material.
Mason et al, in J. Amer. Chem. Soc., 78, 1682 (1956) disclose preparing compounds of the type CCl.sub.3 CHFOR by employing metal fluorides for the exhange reaction with CCl.sub.3 CHClOR. To improve the yield of the fluoroether, Mason et al. teaches dropping the chlorinated ether into potassium fluoride in Nujol.TM. at 140.degree.. However, even under these conditions, polymerization occurred with the use of potassium fluoride. Mercuric fluoride was the preferred reagent.
In Chemistry of Organic Fluorine Compounds, John Wiley & Sons, New York (1976), M. Hudlicky states, that for the replacement of non-activated halogen atoms by fluorine, traditionally potassium fluoride was avoided, and that only recently has it been applied to the replacement of poorly reactive halogen atoms. The conventional solution to this problem has been the application of a suitable solvent. Hudlicky further states that whereas the yields of the reaction of aliphatic halogen derivatives with potassium fluoride without solvent rarely exceed 20-30%, the use of solvents can significantly raise yields. Hudlicky also states that in order to obtain maximum yields, pure and absolutely dry chemicals must be used, and that the reaction is best carried out by heating one mole of the halogen derivative with a 100% excess of potassium fluoride and 700 g of diethylene glycol at a temperature of 125.+-.5.degree. C. with vigorous stirring. Hudlicky further states that compared to potassium fluoride the extent of applications for sodium fluoride is very narrow.
The Kirk-Othmer Encyclopedia of Chemical Technology (1980) states that potassium chloride by-products from reactions with organic chlorides deposit on the potassium fluoride crystal surfaces, significantly retarding the reactions. Polar solvents such as dimethyl sulfoxide or formamides, and rapid stirring are useful in overcoming this drawback.
The need for new and improved procedures for the preparation of certain classes of fluorine containing organic compounds is evident.
It is therefore an object of the present invention to provide a method for the preparation of fluorine containing organic compounds. Still a further object is to provide a method whereby a fluorine containing organic compound may be prepared from a partially chlorinated, brominated or iodinated organic compound. An additional object is to provide a method for preparing a fluorine containing organic compound whereby the formation of undesirable decomposition or side products is substantially avoided. An additional object is to provide a fluorination method which is not subject to certain of the disadvantages set forth above.
It is a further object of the present invention to provide a new and improved process for the production of fluoro or fluoro-chloro substituted organic ether compounds. A further object is the provision of a new and improved method of fluorinating such compounds by means of alkali metal fluorides, and more particularly by means of sodium or potassium fluoride.
Other objects will become apparent from the following specification and claims.